As of 2004, there are more than 129 FDA approved small molecule drugs available for extending life expectancy in at least thirteen types of fatal cancers. However, based on the recent cancer statistics it is projected for 2004 that there will be 1,368,030 new cancer'cases and over 563,700 Americans are expected to succumb to this disease. Additional therapeutic interventions are needed for the treatment of cancer. This project uses target-based assays to discover compounds that will be relevant to treat the four most common solid tumor cancers such as colon/rectal, lung, breast and prostate, which together account for almost 70% of all cancer deaths in the U.S. The Crews component of the NCDDG will explore the natural products from a library of collected sponges and cultured fungi obtained from three sources: sponges, their surrounding water column, and deepwater sediments. A synergist investigation, capitalizing on the strengths of the four additional lab NCDDG programs, will be launched in pursuit of nine specific aims as follows. (1) To continue the study of Indo-Pacific sponges and extracts in our repository for novel biologically active small molecules (MW 400 - 2000) as a source of new anticancer lead compounds. (2) To collect unexplored sponges as a source of additional small molecules. (3) To create a fungal library for saltwater culture from sponges and their surrounding water column. (4) To create a fungal library for saltwater culture from deepwater sediments. (5) To utilize the NIBRI epigenetic and molecular target-based assays to continue the study of current and future active extracts. (6) To shorten the time from discovery of an active extract to defining its active constituents by creating peak libraries for high throughput screening (HTS) guided isolation, followed by state-of-the-art dereplication or structure elucidation. (7) To use Mass Spec approaches for database mining and metabolomic study, in order to expand the chemodiversity of structural lead compounds. (8) To engage in lead optimization. (9) To obtain patent coverage for important new active compounds.